© 2015 The Obesity Society. Objective To conduct an epigenome-wide analysis of DNA methylation and obesity traits. Methods DNA methylation was quantified in CD4+ T-cells using the Illumina Infinium HumanMethylation450 array in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. Methylation at individual cytosine-phosphate-guanine (CpG) sites as a function of body mass index (BMI) and waist circumference (WC), adjusting for age, gender, study site, T-cell purity, smoking, and family structure, was modeled. Results Epigenome-wide significant associations between eight CpG sites and BMI and five CpG sites and WC, successfully replicating the top hits in whole blood samples from the Framingham Heart Study (n-=-2,377) and the Atherosclerosis Risk in Communities study (n-=-2,097), were found. Top findings were in CPT1A (meta-analysis P-=-2.7 × 10-43 for BMI and 9.9 × 10-23 for WC), PHGDH (meta-analysis P-=-2.0 × 10-15 for BMI and 4.0 × 10-9 for WC), CD38 (meta-analysis P-=-6.3 × 10-11 for BMI and 1.6 × 10-12 for WC), and long intergenic non-coding RNA 00263 (meta-analysis P-=-2.2 × 10-16 for BMI and 8.9 × 10-14 for WC), regions with biologically plausible relationships to adiposity. Conclusions This large-scale epigenome-wide study discovered and replicated robust associations between DNA methylation at CpG loci and obesity indices, laying the groundwork for future diagnostic and/or therapeutic applications.